1. Field of the Invention
The present invention relates to catechol derivatives and their use as medicines. More particularly, it relates to catechol derivatives having the ability to induce production and secretion of nerve growth factor (hereinafter abbreviated as NGF) in the local tissue of the brain. The invention also relates to prophylactic and therapeutic preparations containing these derivatives as active ingredients for regressive disorders of the central nervous system.
2. Description of the Prior Art
Basic and clinical researches have been intensively promoted in order to establish early diagnosis and etiologic therapy for various senile diseases with the increasing average span of life in the world. Regressive disorders of the central nervous system are also one of the principal research subjects. Senile Dementia of the Alzheimer Type (hereinafter abbreviated as SDAT), also known as Alzheimer Disease, a typical disease in particular, is becoming a serious social problem as a result of its increase primarily in advanced countries as well as the progressive and tragic course of the disease.
Particularly in recent years, many researchers and clinicians have investigated extensively and yet neither fundamental elucidation of the disease nor effective early diagnosis and therapy have been established. Many pathological findings, however, have been accumulated on the direct cause of failure of immediate memory and disorientation which are characteristic early symptoms of SDAT. According to these findings, the cause is a progressive degeneration in magnocellular cholinergic tracts projecting from the basal forebrain into the cerebral cortex and hippocampus which are the centers of memory and learning, and an accompaning dysfunction in this responsible region. In addition, precursors in acetylcholine biosymthesis or inhibitors of choline esterase were actually administered to SDAT patients as an activation treatment for the brain cholinergic neuron. Cases of partial improvement have been reported whereas generally the results have been not as effective as expected.
NGF has been the subject of many studies since its discovery by R. Levi-Montalcini and S. Cohen et al. It has already been demonstrated by several experiments in physiological chemistry that NGF is an essential factor for the peripheral nervous system relating to differentiation and growth of sensory and sympathetic nerves in the fetus and further, to the survival and maintenance of functions in the sympathetic neurons of an adult.
NGF, however, is a potent biologically active substance even in ultra trace amounts. In spite of long term studies, precise information has not been obtained on its distribution in the tissue and movement which directly prove vital functions. Most recently, development and improvements have been made using the highly sensitive enzyme linked immunosorbent assay (hereinafter abbreviated as ELISA) to identify the active subunit of NGF, e.g. .beta.-NGF (hereinafter simply referred to as NGF). Thus satisfactory detection-sensitivity and specificity for this examination have been attained [S. Furukawa et al., J. Neurochem., 40, 734-744 (1983); S. Korshing and H. Thoenen, Proc. Natl. Acad. Sci. U.S.A., 80, 3513-3516 (1983)].
Further, the NGF gene has been cloned and structure is analyzed. A method for determining messenger RNA (hereinafter abbreviated as m RNA) for .beta.-NGF has been established using its complemental DNA (hereinafter abbreviated as cDNA) as a probe [D. L. Shelton and L. F. Reichardt, Proc. Natl. Acad. Sci. U.S.A., 81, 7951-7955 (1984); R. Heumann et al., EMBO J., 3, 3183-3189 (1984)].
By applying these procedures, a clear positive correlation has been demonstrated between the grade of sympathetic innervation in the peripheral nervous system and gene expression of NGF in the innervated tissue.
More surprisingly, NGF has also been detected in the central nervous system of rats, particularly in hippocampus, neocortex, and basal forebrain, e.g. septum, olfatory bulb, diagonal band of Broca, and nucleus basalis magnocellularis. In addition, its mRNA content has been found at a high level in the hippocampus and neocortex. On the other hand, the NGF content in the septum of the basal forebrain has been found at a low level as in other regions of the brain where no NGF antigen was detected [S. Korshing et al., EMBO J., 4, 1389-1393 (1985)]. Thereafter the results have been successively traced by other research groups [D. L. Shelton and L. F. Reichardt, Proc. Natl. Acad. Sci. U.S.A., 83, 2714-2718 (1986); S. R. Whittemore et al., Proc. Natl. Acad. Sci. U.S.A., 83, 817-821 (1986)].
According to these results, the NGF gene is expressed not only in the peripheral nervous system, but in the central nervous system as well. Furthermore, it was demonstrated that NGF is produced and secreted in the innervating regions of the chlorinergic tracts projecting from the origins of the basal forebrain to the neocortex and hippocampus, the centers of memory and learning, and then taken up at the nerve endings and transported in a retrograde manner through axons to reach somata in the origins. NGF has already been proven by a series of physiological experiments to be an essential factor for the survival and maintenance of functions in the chlorinergic tracts. These results have demonstrated the assumption that NGF has a specific function as a "neurotropic factor" also in the central nervous system. Thereafter the experiment has been traced by several research groups and has also been proven by investigation of NGF receptors and their distribution in the brain.
The present inventors have investigated the function of NGF as the neurotropic factor in the central nervous system. As discussed in the literature, summarized above, the disorders in memory and learning which are the early symptoms of SDAT are directly caused by the progressive degeneration of cholinergic tracts and consequent dysfunction of brain domains under their control.
The inventors, however, now believe that the failure of production and secretion of NGF in particular regions of brain can be the truly fundamental cause of early symptoms in SDAT. This is because conventional symptomatic trials against SDAT, such as supplementation and/or availability improvement therapies with acetylcholine, have been made without any remarkable result. On the other hand, it is believed that effective therapy may be realized if the functionally vicious cycle between responsible nerves and regions under their control could be broken by maintaining the production and secretion of NGF in the cerebral cortex and hippocampus.
Procedures for preparing human-type .beta.-NGF in a large amounts have already been developed by gene-manipulation, yet many pharmacological and pharmaceutical limitations still exist on achieving supplemental therapy of NGF itself, which is a protein having a molecular weight of above 10,000. To date, there has been no application of NGF to the central nervous system.
It is important from the above viewpoint to investigate low molecular weight compounds capable of inducing the production and secretion of NGF in particular tissues to be used as therapeutics for substantial and effective supplemental NGF therapy. The present inventors have already reported catechol derivatives having such activity (Ikeda: U.S. patent application Ser. No. 07/098554). There are also reports of Furukawa et al. [Y. Furukawa et al., J. Boil. Chem., 261, 6039 (1986) and FEBS Letters, 208, 258(1986)]